Grupo de Estudos em Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, Av. Trabalhador Sancarlense 400, 13560-970, São Carlos-SP, Brazil.
Eur J Med Chem. 2010 Dec;45(12):5899-909. doi: 10.1016/j.ejmech.2010.09.055. Epub 2010 Oct 7.
The enzyme dihydroorotate dehydrogenase (DHODH) has been suggested as a promising target for the design of trypanocidal agents. We report here the discovery of novel inhibitors of Trypanosoma cruzi DHODH identified by a combination of virtual screening and ITC methods. Monitoring of the enzymatic reaction in the presence of selected ligands together with structural information obtained from X-ray crystallography analysis have allowed the identification and validation of a novel site of interaction (S2 site). This has provided important structural insights for the rational design of T. cruzi and Leishmania major DHODH inhibitors. The most potent compound (1) in the investigated series inhibits TcDHODH enzyme with Kiapp value of 19.28 μM and possesses a ligand efficiency of 0.54 kcal mol(-1) per non-H atom. The compounds described in this work are promising hits for further development.
二氢乳清酸脱氢酶（DHODH）已被认为是设计杀变形虫药物的有前途的靶点。我们在此报告了通过虚拟筛选和 ITC 方法相结合发现的新型 Trypanosoma cruzi DHODH 抑制剂。在存在选定配体的情况下监测酶反应，并结合从 X 射线晶体学分析获得的结构信息，确定并验证了一个新的相互作用位点（S2 位点）。这为合理设计 T. cruzi 和 Leishmania major DHODH 抑制剂提供了重要的结构见解。在所研究的系列中，最有效的化合物（1）以 19.28 μM 的 Kiapp 值抑制 TcDHODH 酶，并且具有 0.54 kcal mol(-1)每非 H 原子的配体效率。本文所述的化合物是进一步开发的有希望的命中物。
